CN102675225A - Synthesis method of erlotinib hydrochloride - Google Patents
Synthesis method of erlotinib hydrochloride Download PDFInfo
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- CN102675225A CN102675225A CN2012101524518A CN201210152451A CN102675225A CN 102675225 A CN102675225 A CN 102675225A CN 2012101524518 A CN2012101524518 A CN 2012101524518A CN 201210152451 A CN201210152451 A CN 201210152451A CN 102675225 A CN102675225 A CN 102675225A
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- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960005073 erlotinib hydrochloride Drugs 0.000 title claims abstract description 40
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 137
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical group NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- UISZKHSCSVDZMV-UHFFFAOYSA-N acetylene nitrobenzene Chemical group C#C.[N+](=O)([O-])C1=CC=CC=C1 UISZKHSCSVDZMV-UHFFFAOYSA-N 0.000 claims abstract description 22
- WWXMVRYHLZMQIG-SNAWJCMRSA-N 3-nitrocinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC([N+]([O-])=O)=C1 WWXMVRYHLZMQIG-SNAWJCMRSA-N 0.000 claims abstract description 19
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims abstract description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
- 229910052987 metal hydride Inorganic materials 0.000 claims abstract description 10
- 150000004681 metal hydrides Chemical class 0.000 claims abstract description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- 238000001035 drying Methods 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 239000003960 organic solvent Substances 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- GOLFLVGUAVKJIC-UHFFFAOYSA-N 2-bromo-3-(3-nitrophenyl)propanoic acid Chemical compound OC(=O)C(Br)CC1=CC=CC([N+]([O-])=O)=C1 GOLFLVGUAVKJIC-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 21
- 239000012141 concentrate Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000000967 suction filtration Methods 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 13
- YOTXPVFRAUVUQD-PLNGDYQASA-N 1-[(z)-2-bromoethenyl]-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(\C=C/Br)=C1 YOTXPVFRAUVUQD-PLNGDYQASA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 9
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 9
- 238000000638 solvent extraction Methods 0.000 claims description 9
- YOTXPVFRAUVUQD-UHFFFAOYSA-N 1-(2-bromoethenyl)-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(C=CBr)=C1 YOTXPVFRAUVUQD-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- -1 tetracol phenixin Chemical compound 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical group [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract 2
- 239000005977 Ethylene Substances 0.000 abstract 2
- AYUJMWVMPDGXFF-UHFFFAOYSA-N 2,3-dibromo-3-(3-nitrophenyl)propanoic acid Chemical compound OC(=O)C(Br)C(Br)C1=CC=CC([N+]([O-])=O)=C1 AYUJMWVMPDGXFF-UHFFFAOYSA-N 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000006114 decarboxylation reaction Methods 0.000 abstract 1
- 238000007269 dehydrobromination reaction Methods 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 37
- 238000003756 stirring Methods 0.000 description 36
- 239000007788 liquid Substances 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000006837 decompression Effects 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 238000007710 freezing Methods 0.000 description 6
- 230000008014 freezing Effects 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N ethyl acetylene Natural products CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- JXMZUNPWVXQADG-UHFFFAOYSA-N 1-iodo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1I JXMZUNPWVXQADG-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N COCCOc1cc2c(Nc3cccc(C#C)c3)ncnc2cc1OCCOC Chemical compound COCCOc1cc2c(Nc3cccc(C#C)c3)ncnc2cc1OCCOC AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
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- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- MTSNDBYBIZSILH-UHFFFAOYSA-N n-phenylquinazolin-4-amine Chemical class N=1C=NC2=CC=CC=C2C=1NC1=CC=CC=C1 MTSNDBYBIZSILH-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
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Abstract
The invention relates to a synthesis method of erlotinib hydrochloride, which comprises the following technological process of: a, synthesizing m-nitrocinnamic acid by taking m-nitrobenzaldehyde as raw material; b, carrying out bromine addition to obtain 2, 3-dibromo-3-(3'-nitrophenyl) propanoic acid; c, carrying out decarboxylation and dehydrobromination to obtain (Z)-beta-bromo-(3'-nitrophenyl) ethylene; d, enabling the (Z)-beta-bromo-(3'-nitrophenyl) ethylene to have reaction with metal hydride to obtain m-nitrobenzene acetylene; e, reducing to obtain m-aminophenyl acetylene; and f, enabling the m-aminophenyl acetylene to have reaction with 4-chloro-6, 7-bi-(2-methoxy-ethoxy)-quinazoline, to obtain the erlotinib hydrochloride. The raw materials of the synthesis method are easy to obtain and low in cost, and the synthesis method is mild in reaction conditions, simple and convenient in operation, higher in yield and suitable for amplification.
Description
Technical field
The present invention relates to a kind of compound method of Erlotinib hydrochloride, belong to the technical field of medication preparation.
Background technology
Erlotinib hydrochloride (erlotinib hydrochloride), commodity are called tower Western method (Tarceva), and chemical name is N-(3-Phenylacetylene)-6,7-two (the own oxygen of methoxy)-4-quinazoline amine hydrochlorate, its structural formula is seen formula 1:
Formula 1 Erlotinib hydrochloride molecular formula
Erlotinib hydrochloride is the oral anti-cancer agent of 4-anilinoquinazoline class by Luo Shi (Roche), the common research and development of west (OSI) biopharmaceutical company difficult to understand and Genentech (Genentech) drugmaker.2004, the drugs approved by FDA Erlotinib hydrochloride was used to treat local late period and transitivity nonsmall-cell lung cancer, 2005, is approved for the treatment of carcinoma of the pancreas again.
Erlotinib Hydrochloride is an antitumour drug based on new mechanism of action--the target therapeutic agent of tumour; Reversible and the selectively acting of target is in the EGF-R ELISA hypotype (EGFR-TK) of tyrosine kinase receptor; Its mechanism of action is in cell and substrate competition, suppresses the EGFR-TK phosphorylation, the transduction of blocking-up tumour cell signal; Suppress the growth of tumour cell, induce its accent to die.
About the structure of Erlotinib hydrochloride molecule, common mode is to take 4-chloro-6, and 7-two-(2-methoxy ethoxy)-quinazoline and m-aminophenyl acetylene generation nucleophilic substitution reaction are accomplished.U.S. Pat 5747498, Chinese patent CN101463013A, document Heterocy
-cles [2007; 71 (1): 39-48] and Tetrahedron [2010; 66 (4): 962-968] all related to 4-chloro-6, the compound method of 7-two-(2-methoxy ethoxy)-quinazoline, but as another key intermediate of Erlotinib hydrochloride; The compound method report of m-aminophenyl acetylene is less, and it mainly prepares through following two kinds of methods:
(1) Urazoe etc. has reported a kind of compound method of m-aminophenyl acetylene at US20060224016; With 3-bromaniline and 2-methyl-3-crotonylene alcohol is raw material; The Sonogashira linked reaction takes place under the catalysis of triphenylphosphine, palladium and cuprous iodide generate 1-(3-aminophenyl)-3-methyl-3-hydroxyl-ethyl acetylene midbody earlier; The latter heats the generation elimination reaction and obtains m-aminophenyl acetylene under the highly basic condition; The raw material valency that this method is used is high rare, and is easy to generate polymeric by-products in the elimination reaction process, influences yield.
(2) John Spencer etc. is at Tetrahedron [2008; 64 (44): 10195 – 10200] reported the another kind of compound method of m-aminophenyl acetylene; Be raw material promptly with a nitro iodobenzene and trimethyl silicane ethyl-acetylene; Coupling obtains 3-nitrophenyl-trimethyl silicane ethyl-acetylene under two (triphenylphosphine) palladium chloride (II) and cuprous iodide catalysis, and the latter obtains m-aminophenyl acetylene through hexacarbonylmolybdenum, DBU reduction under microwave radiation.The raw materials used valency of this method is high rare, complex operation, and yield is lower, only is suitable for laboratory study.
Therefore, the objective of the invention is at first to propose a kind of compound method of m-aminophenyl acetylene, then with 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline reaction obtains Erlotinib hydrochloride.
Summary of the invention
For overcoming disadvantages of background technology, the object of the present invention is to provide a kind of yield high, easy and simple to handle, the compound method of a kind of Erlotinib hydrochloride that manufacturing cost is low.
The step of the compound method of Erlotinib hydrochloride is following:
A. with mol ratio be 1:1~2:1.5~3 m-nitrobenzaldehyde, weak base and diacetyl oxide 20~180 ℃ the reaction 5~15 hours, the cooling, pour in the strong base solution; Use organic solvent extraction; Water layer is transferred PH=2~3 with concentrated hydrochloric acid under the ice bath cooling, suction filtration, frozen water washing; Drying obtains m-nitro-cinnamic acid;
B. with mol ratio be m-nitro-cinnamic acid and the bromine of 1:1~3 in organic solvent in 20~100 ℃ of reactions 2~10 hours down, steaming desolventizes, recrystallization obtains 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid;
C. with 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid are dissolved in the N, and ice bath is cooled to 0 ℃; Slowly drip triethylamine, rise to room temperature after dropwising, stirred 5~15 hours; Add water, use organic solvent extraction, washing; Drying concentrates and obtains (Z)-β-bromo-(3 '-nitrophenyl)-ethene; 2, the mol ratio of 3-two bromo-3-(3 '-nitrophenyl) propionic acid and triethylamine is 1:1~3;
D. (Z)-β-bromo-(3 '-nitrophenyl)-ethene is dissolved in the N, adds metal hydride under 0~50 ℃ in batches, add afterreaction after 1~5 hour, add water, use organic solvent extraction, washing, drying concentrates and obtains m-nitrobenzene acetylene; (Z)-mol ratio of β-bromo-(3 '-nitrophenyl)-ethene and metal hydride is 1:1~5;
E. m-nitrobenzene acetylene is dissolved in the organic solvent, joins in the sodium sulfide solution and reacted cooling, extraction, drying, the concentrated m-aminophenyl acetylene that obtains 2~5 hours in 20~100 ℃; The mol ratio of m-nitrobenzene acetylene and sodium sulphite is 1:1~10;
F. be the 4-chloro-6 of 1:1~1.5 with mol ratio, 7-two-(2-methoxy ethoxy)-quinazoline and m-aminophenyl acetylene in 50~100 ℃ of reactions 2~15 hours, cool off in organic solvent, suction filtration, and washing, drying obtains Erlotinib hydrochloride.
In a step, described weak base is yellow soda ash, salt of wormwood, sodium-acetate, Potassium ethanoate; Said highly basic is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate; Said organic solvent is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene,toluene,xylene.
In the b step, described organic solvent is methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, acetate or N;
In the c step, described organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
In the d step, described metal hydride is lithium hydride, sodium hydride, potassium hydride KH or hydrolith; Said organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
Among the step e, described organic solvent is one or more in methyl alcohol, ethanol, propyl alcohol, butanols, dioxane, terepthaloyl moietie, the USP Kosher.
In step f, described organic solvent is the Fatty Alcohol(C12-C14 and C12-C18) of C1~C10, like in methyl alcohol, ethanol, Virahol, the butanols one or more.
The invention has the beneficial effects as follows that employed raw material and reagent are common in the building-up process is easy to get, each goes on foot the reaction conditions gentleness, and not harsh to equipment requirements, yield is higher.Reaction respectively goes on foot the midbody separate easily and purifies, and convenient post-treatment is easy to carry out suitability for industrialized production.
Description of drawings
Accompanying drawing be Erlotinib hydrochloride proton nmr spectra (1H-NMR, DMSO-d6).
Embodiment
The technical scheme that the present invention adopts is following:
The step of the compound method of Erlotinib hydrochloride is following:
A. with mol ratio be 1:1~2:1.5~3 m-nitrobenzaldehyde, weak base and diacetyl oxide 20~180 ℃ the reaction 5~15 hours, the cooling, pour in the strong base solution; Control PH ≈ 12 uses organic solvent extraction, and water layer is transferred PH=2~3 with concentrated hydrochloric acid under the ice bath cooling; Suction filtration; The frozen water washing, drying obtains m-nitro-cinnamic acid;
B. with mol ratio be m-nitro-cinnamic acid and the bromine of 1:1~3 in organic solvent in 20~100 ℃ of reactions 2~10 hours down, steaming desolventizes, recrystallization obtains 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid;
C. with 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid are dissolved in the N, and ice bath is cooled to 0 ℃; Slowly drip triethylamine, drop to 2, the mol ratio of 3-two bromo-3-(3 '-nitrophenyl) propionic acid and triethylamine is to rise to room temperature behind 1:1~3; Stirred 5~15 hours, and added water, use organic solvent extraction; Washing, drying concentrates and obtains (Z)-β-bromo-(3 '-nitrophenyl)-ethene;
D. (Z)-β-bromo-(3 '-nitrophenyl)-ethene is dissolved in the N; The mol ratio that in batches adds metal hydride to (Z)-β-bromo-(3 '-nitrophenyl)-ethene and metal hydride under 0~50 ℃ is 1:1~5, reacts after 1~5 hour, adds water; Use organic solvent extraction; Washing, drying concentrates and obtains m-nitrobenzene acetylene;
E. m-nitrobenzene acetylene is dissolved in the organic solvent, joins that the mol ratio to m-nitrobenzene acetylene and sodium sulphite is 1:1~10 in the sodium sulfide solution, in 20~100 ℃ of reactions 2~5 hours, cooling, extraction, drying concentrates and obtains m-aminophenyl acetylene;
F. be the 4-chloro-6 of 1:1~1.5 with mol ratio, 7-two-(2-methoxy ethoxy)-quinazoline and m-aminophenyl acetylene in 50~100 ℃ of reactions 2~15 hours, cool off in organic solvent, suction filtration, and washing, drying obtains Erlotinib hydrochloride.
In a step, described weak base is yellow soda ash, salt of wormwood, sodium-acetate, Potassium ethanoate; Said highly basic is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate; Said organic solvent is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene,toluene,xylene.
In the b step, described organic solvent is methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, acetate or N;
In the c step, described organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
In the d step, described metal hydride is lithium hydride, sodium hydride, potassium hydride KH or hydrolith; Said organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
Among the step e, described organic solvent is one or more in methyl alcohol, ethanol, propyl alcohol, butanols, dioxane, terepthaloyl moietie, the USP Kosher.
In step f, described organic solvent is the Fatty Alcohol(C12-C14 and C12-C18) of C1~C10, like in methyl alcohol, ethanol, Virahol, the butanols one or more.
Further specify the present invention through embodiment below, but can not limit content of the present invention.Although the present invention has been carried out detailed explanation with reference to preferred embodiment; Those of ordinary skill in the art is to be understood that it and still can makes amendment or be equal to replacement technical scheme of the present invention, and these modifications or be equal to replacement and also can not make amended technical scheme break away from the spirit and the scope of technical scheme of the present invention.
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), sodium acetate, anhydrous 16.4g (0.2mol) and diacetyl oxide 30.6g (0.3mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 15 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% aqueous sodium hydroxide solution, and stirring extracted with methylene dichloride (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 33.2g, the yield 86% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 33g (0.17mol), chloroform 150ml in the 250ml reaction flask, add bromine 27.16g (0.17mol) after the stirring and dissolving, the temperature rising reflux reaction is 6 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes chloroform, and residue obtains white solid 48.2g with the ethylene dichloride recrystallization, yield 80%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 40g (0.113mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 11.4g (0.113mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with ETHYLE ACETATE (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 19.63g, yield 75.7%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 19g (0.08mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH 3.97g (0.08mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with methylene dichloride (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 9.4g, yield 80%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 15.35g (0.064mol) and 100ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml methyl alcohol with m-nitrobenzene acetylene 9.4g (0.064mol); Join in the reaction flask, reacted 6 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 6.2g, yield 83%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 16.68g (0.053mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 6.2g (0.053mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 20.5g, yield 90%.Identify that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
Embodiment 2
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), sodium acetate, anhydrous 32.8g (0.4mol) and diacetyl oxide 61.25g (0.6mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 12 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% aqueous sodium hydroxide solution, and stirring extracted with ethylene dichloride (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 34.38g, the yield 89% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 33g (0.17mol), chloroform 150ml in the 250ml reaction flask, add bromine 81.5g (0.51mol) after the stirring and dissolving, the temperature rising reflux reaction is 8 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes tetracol phenixin, and residue obtains white solid 51.24g with the ethylene dichloride recrystallization, yield 85%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 50g (0.141mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 42.8g (0.423mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with methylene dichloride (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 27.8g, yield 86%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 27.55g (0.12mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH 28.8g (0.6mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with chloroform (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 15.52g, yield 88%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 240g (1mol) and 150ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml ethanol with m-nitrobenzene acetylene 15g (0.1mol); Join in the reaction flask, reacted 3 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 9.84g, yield 84%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 17.54g (0.0557mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 9.8g (0.0836mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 20.73g, yield 88%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
Embodiment 3
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), sodium acetate, anhydrous 24.6g (0.3mol) and diacetyl oxide 25.5g (0.25mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 15 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% aqueous sodium hydroxide solution, and stirring extracted with methylene dichloride (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 35.15g, the yield 91% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 33g (0.17mol), chloroform 150ml in the 250ml reaction flask, add bromine 32.6g (0.204mol) after the stirring and dissolving, the temperature rising reflux reaction is 6 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes chloroform, and residue obtains white solid 53g with the ethylene dichloride recrystallization, yield 88%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 50g (0.141mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 28.53g (0.282mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with ETHYLE ACETATE (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 28.16g, yield 87%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 27.55g (0.12mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH 11.52g (0.24mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with methylene dichloride (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 15.52g, yield 88%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 120g (0.5mol) and 100ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml methyl alcohol with m-nitrobenzene acetylene 15g (0.1mol); Join in the reaction flask, reacted 3 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 10.54g, yield 90%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 22.4g (0.071mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 10g (0.085mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 27.16g, yield 89%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
Embodiment 4
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), Glacial acetic acid potassium 19.62g (0.2mol) and diacetyl oxide 61.25g (0.6mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 16 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% potassium hydroxide aqueous solution, and stirring extracted with chloroform (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 32.83g, the yield 85% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 30g (0.155mol), tetracol phenixin 150ml in the 250ml reaction flask, add bromine 24.8g (0.155mol) after the stirring and dissolving, the temperature rising reflux reaction is 6 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes chloroform, and residue obtains white solid 47.8g with the ethylene dichloride recrystallization, yield 87%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 45g (0.127mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 12.8g (0.127mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with methylene dichloride (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 23.03g, yield 79%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 23g (0.1mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH4.8g (0.1mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with methylene dichloride (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 11.9g, yield 81%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 17.9g (0.075mol) and 100ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml methyl alcohol with m-nitrobenzene acetylene 11g (0.075mol); Join in the reaction flask, reacted 6 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 7.03g, yield 80%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 18.89g (0.06mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 7g (0.06mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 22.7g, yield 88%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), sodium acetate, anhydrous 32.8g (0.4mol) and diacetyl oxide 61.25g (0.6mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 15 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% aqueous sodium hydroxide solution, and stirring extracted with methylene dichloride (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 33.6g, the yield 87% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 33g (0.17mol), chloroform 150ml in the 250ml reaction flask, add bromine 81.5g (0.51mol) after the stirring and dissolving, the temperature rising reflux reaction is 6 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes chloroform, and residue obtains white solid 51.2g with the ethylene dichloride recrystallization, yield 85%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 50g (0.141mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 42.8g (0.423mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with chloroform (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 28.48g, yield 88%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 28g (0.12mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH 28.8g (0.6mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with chloroform (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 15g, yield 85%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 240g (1mol) and 100ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml methyl alcohol with m-nitrobenzene acetylene 15g (0.1mol); Join in the reaction flask, reacted 2 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 10.19g, yield 87%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 17.9g (0.057mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 10g (0.085mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 22.05g, yield 90%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
(1) preparation of m-nitro-cinnamic acid
Add m-nitrobenzaldehyde 30.22g (0.2mol), sodium acetate, anhydrous 16.4g (0.2mol) and diacetyl oxide 30.6g (0.3mol) in the 250ml reaction flask, be heated to 180 ℃ of reactions 15 hours.Reaction finishes postcooling to room temperature, and reaction solution is poured in 300ml 10% aqueous sodium hydroxide solution, and stirring extracted with methylene dichloride (150ml * 3) after half a hour; Divide water-yielding stratum, using concentrated hydrochloric acid to transfer pH value is 2~3, separates out a large amount of solids; Suction filtration; Filter cake washs 2~3 times with frozen water, dry white solid 32g, the yield 83% of getting.
The preparation of (2) 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid
Add m-nitro-cinnamic acid 33g (0.17mol), chloroform 150ml in the 250ml reaction flask, add bromine 81.5g (0.51mol) after the stirring and dissolving, the temperature rising reflux reaction is 6 hours gradually.Reaction finishes afterreaction liquid and concentrates earlier, steams and removes chloroform, and residue obtains white solid 52.78g with the ethylene dichloride recrystallization, yield 88%.
(3) (Z)-preparation of β-bromo-(3 '-nitrophenyl)-ethene
Add 2 in the 250ml reaction flask; 3-two bromo-3-(3 '-nitrophenyl) propionic acid 50g (0.141mol) and DMF (160ml); After the stirring and dissolving in cryosel is bathed temperature reduce to 0 ℃; Slowly drip triethylamine 14.26g (0.141mol), dropwise the back and under this temperature, continue to stir 1 hour, after rose to room temperature reaction gradually 8 hours.After reaction finished, reaction solution was poured in the 500ml water, extracts with ETHYLE ACETATE (250ml * 3); Use the washing of saturated sodium bicarbonate aqueous solution (300ml * 3) and water (300ml * 3) successively; Anhydrous sodium sulfate drying, decompression steams solvent and obtains yellowish brown liquid 25.25g, yield 78%.
(4) preparation of m-nitrobenzene acetylene
In the 250ml reaction flask, add (Z)-β-bromo-(3 '-nitrophenyl)-ethene 25g (0.1mol) and dry DMF (100ml), the ice-water bath cooling adds 50%NaH 24g (0.5mol) down in batches, finishes continued stirring reaction 1h; The TLC detection reaction finishes; Reaction solution is poured in 400ml 5% aqueous ammonium chloride solution, and with methylene dichloride (150ml * 3) extraction, organic layer water (300ml * 3) washs behind the stirring 10min; Anhydrous sodium sulfate drying; Decompression steams solvent and obtains weak yellow liquid 12.5g, yield 85%, and freezing curing records 26~27 ℃ of fusing points.
(5) preparation of m-aminophenyl acetylene
Add nine hydrated sodium sulfide 24g (0.1mol) and 100ml water in the 250ml reaction flask, 80 ℃ of heating for dissolving to solution temperatures are dissolved in 20ml methyl alcohol with m-nitrobenzene acetylene 15g (0.1mol); Join in the reaction flask, reacted 6 hours, stop heating after the TLC detection reaction finishes; Extract with toluene (100ml * 3); Anhydrous sodium sulfate drying concentrates and obtains light yellow liquid 9.37g, yield 80%.
(6) preparation of Erlotinib hydrochloride
Add 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline 16.12g (0.05mol), 100ml Virahol in the 250ml reaction flask; M-aminophenyl acetylene 9g (0.0768mol), reflux 5 hours, reaction finishes; Cooling, suction filtration, filter cake is with petroleum ether 3 times; Drying obtains Erlotinib hydrochloride 19.6g, yield 89%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (DMSO-d6) δ 3.40 (s, 6H), 3,79 (s, 4H), 4.30 (s; 1H), 4.35 (s, 4H), 7.33 (s, 1H), 7.40-7.42 (d, 1H); 7.49-7.53 (t, 1H), 7.76-7.78 (s, 1H), 7,87 (s, 1H); 8.24 (s, 1H), 8.83 (s, 1H), 11.10 (s, 1H).
(1H-NMR DMSO-d6) sees accompanying drawing to the proton nmr spectra of Erlotinib hydrochloride.
Claims (7)
1. the compound method of an Erlotinib hydrochloride is characterized in that the step of this method is following:
A. with mol ratio be 1:1~2:1.5~3 m-nitrobenzaldehyde, weak base and diacetyl oxide 20~180 ℃ the reaction 5~15 hours, the cooling, pour in the strong base solution; Use organic solvent extraction; Water layer is transferred PH=2~3 with concentrated hydrochloric acid under the ice bath cooling, suction filtration, frozen water washing; Drying obtains m-nitro-cinnamic acid;
B. with mol ratio be m-nitro-cinnamic acid and the bromine of 1:1~3 in organic solvent in 20~100 ℃ of reactions 2~10 hours down, steaming desolventizes, recrystallization obtains 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid;
C. with 2,3-two bromo-3-(3 '-nitrophenyl) propionic acid are dissolved in the N, and ice bath is cooled to 0 ℃; Slowly drip triethylamine, rise to room temperature after dropwising, stirred 5~15 hours; Add water, use organic solvent extraction, washing; Drying concentrates and obtains (Z)-β-bromo-(3 '-nitrophenyl)-ethene; 2, the mol ratio of 3-two bromo-3-(3 '-nitrophenyl) propionic acid and triethylamine is 1:1~3;
D. (Z)-β-bromo-(3 '-nitrophenyl)-ethene is dissolved in the N, adds metal hydride under 0~50 ℃ in batches, added afterreaction 1~5 hour, add water, use organic solvent extraction, washing, drying concentrates and obtains m-nitrobenzene acetylene; (Z)-mol ratio of β-bromo-(3 '-nitrophenyl)-ethene and metal hydride is 1:1~5;
E. m-nitrobenzene acetylene is dissolved in the organic solvent, joins in the sodium sulfide solution and reacted cooling, extraction, drying, the concentrated m-aminophenyl acetylene that obtains 2~5 hours in 20~100 ℃; The mol ratio of m-nitrobenzene acetylene and sodium sulphite is 1:1~10;
F. be the 4-chloro-6 of 1:1~1.5 with mol ratio, 7-two-(2-methoxy ethoxy)-quinazoline and m-aminophenyl acetylene in 50~100 ℃ of reactions 2~15 hours, cool off in organic solvent, suction filtration, and washing, drying obtains Erlotinib hydrochloride.
2. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: in a step, described weak base is yellow soda ash, salt of wormwood, sodium-acetate, Potassium ethanoate; Said highly basic is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate; Said organic solvent is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene,toluene,xylene.
3. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: in the b step, described organic solvent is methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, acetate or N.
4. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: in the c step, described organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
5. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: in the d step, described metal hydride is lithium hydride, sodium hydride, potassium hydride KH or hydrolith; Said organic solvent is ETHYLE ACETATE, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene or YLENE.
6. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: among the step e, described organic solvent is one or more in methyl alcohol, ethanol, propyl alcohol, butanols, dioxane, terepthaloyl moietie, the USP Kosher.
7. the compound method of Erlotinib hydrochloride according to claim 1, it is characterized in that: in step f, described organic solvent is one or more in methyl alcohol, ethanol, Virahol, the butanols.
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